This invention relates to blood component storage solutions and more particularly to blood component storage solutions containing a photosensitizer for viral inactivation.
Contamination of blood supplies with infectious microorganisms such as HIV, hepatitis and other viruses and bacteria presents a serious health hazard for those who must receive transfusions of whole blood or administration of various blood components such as platelets, red cells, blood plasma, Factor VIII, plasminogen, fibronectin, anti-thrombin III, cryoprecipitate, human plasma protein fraction, albumin, immune serum globulin, prothrombin complex plasma growth hormones, and other components isolated from blood. Blood screening procedures may miss contaminants, and sterilization procedures which do not damage cellular blood components but effectively inactivate all infectious viruses and other microorganisms have not heretofore been available.
Solvent detergent methods of blood component decontamination work by dissolving phospholipid membranes surrounding viruses such as HIV, and do not damage protein components of blood; however, if blood cells are present, such methods cannot be used because of damage to cell membranes.
The use of photosensitizers, compounds which absorb light of a defined wavelength and transfer the absorbed energy to an energy acceptor, has been proposed for blood component sterilization. For example, European Patent application 196,515 published Oct. 8, 1986, suggests the use of non-endogenous photosensitizers such as porphyrins, psoralens, acridine, toluidines, flavine (acriflavine hydrochloride), phenothiazine derivatives, and dyes such as neutral red, and methylene blue, as blood additives. Protoporphyrin, which occurs naturally within the body, can be metabolized to form a photosensitizer; however, its usefulness is limited in that it degrades desired biological activities of proteins. Chlorpromazine, is also exemplified as one such photosensitizer; however its usefulness is limited by the fact that it should be removed from any fluid administered to a patient after the decontamination procedure because it has a sedative effect.
Goodrich, R. P., et al. (1997), xe2x80x9cThe Design and Development of Selective, Photoactivated Drugs for Sterilization of Blood Products,xe2x80x9d Drugs of the Future 22:159-171 provides a review of some photosensitizers including psoralens, and some of the issues of importance in choosing photosensitizers for decontamination of blood products. The use of texaphyrins for DNA photocleavage is described in U.S. Pat. No. 5,607,924 issued Mar. 4, 1997 and U.S. Pat. No. 5,714,328 issued Feb. 3, 1998 to Magda et al. The use of sapphyrins for viral deactivation is described in U.S. Pat. No. 5,041,078 issued Aug. 20, 1991 to Matthews, et al. Inactivation of extracellular enveloped viruses in blood and blood components by Phenthiazin-5-ium dyes plus light is described in U.S. Pat. No. 5,545,516 issued Aug. 13, 1996 to Wagner. The use of porphyrins, hematoporphyrins, and merocyanine dyes as photosensitizing agents for eradicating infectious contaminants such as viruses and protozoa from body tissues such as body fluids is disclosed in U.S. Pat. No. 4,915,683 issued Apr. 10, 1990 and related U.S. Pat. No. 5,304,113 issued Apr. 19, 1994 to Sieber et al. The mechanism of action of such photosensitizers is described as involving preferential binding to domains in lipid bilayers, e.g. on enveloped viruses and some virus-infected cells. Photoexcitation of membrane-bound agent molecules leads to the formation of reactive oxygen species such as singlet oxygen which causes lipid peroxidation. A problem with the use of such photosensitizers is that they attack cell membranes of desirable components of fluids to be decontaminated, such as red blood cells, and the singlet oxygen also attacks desired protein components of fluids being treated. U.S. Pat. No. 4,727,027 issued Feb. 23, 1988 to Wiesehahn, G. P., et al. discloses the use of furocoumarins including psoralen and derivatives for decontamination of blood and blood products, but teaches that steps must be taken to reduce the availability of dissolved oxygen and other reactive species in order to inhibit denaturation of biologically active proteins. Photoinactivation of viral and bacterial blood contaminants using halogenated coumarins is described in U.S. Pat. No. 5,516,629 issued May 14, 1996 to Park, et al. U.S. Pat. No. 5,587,490 issued Dec. 24, 1996 to Goodrich Jr., R. P., et al. and U.S. Pat. No. 5,418,130 to Platz, et al. disclose the use of substituted psoralens for inactivation of viral and bacterial blood contaminants. The latter patent also teaches the necessity of controlling free radical damage to other blood components. U.S. Pat. No. 5,654,443 issued Aug. 5, 1997 to Wollowitz et al. teaches new psoralen compositions used for photodecontamination of blood. U.S. Pat. No. 5,709,991 issued Jan. 20, 1998 to Lin et al. teaches the use of psoralen for photodecontamination of platelet preparations and removal of psoralen afterward. U.S. Pat. No. 5,120,649 issued Jun. 9, 1992 and related U.S. Pat. No. 5,232,844 issued Aug. 3, 1993 to Horowitz, et al., also disclose the need for the use of xe2x80x9cquenchersxe2x80x9d in combination with photosensitizers which attack lipid membranes, and U.S. Pat. No. 5,360,734 issued Nov. 1, 1994 to Chapman et al. also addresses this problem of prevention of damage to other blood components.
Photosensitizers which attack nucleic acids are known to the art. U.S. Pat. No. 5,342,752 issued Aug. 30, 1994 to Platz et al. discloses the use of compounds based on acridine dyes to reduce parasitic contamination in blood matter comprising red blood cells, platelets, and blood plasma protein fractions. These materials, although of fairly low toxicity, do have some toxicity e.g. to red blood cells. U.S. Pat. No. 5,798,238 to Goodrich, Jr., et al., discloses the use of quinolone and quinolone compounds for inactivation of viral and bacterial contaminants.
Binding of DNA with photoactive agents has been exploited in processes to reduce lymphocytic populations in blood as taught in U.S. Pat. No. 4,612,007 issued Sep. 16, 1986 and related U.S. Pat. No. 4,683,889 issued Aug. 4, 1987 to Edelson.
Riboflavin (7,8-dimethyl-10-ribityl isoalloxazine) has been reported to attack nucleic acids. Photoalteration of nucleic acid in the presence of riboflavin is discussed in Tsugita, A, et al. (1965), xe2x80x9cPhotosensitized inactivation of ribonucleic acids in the presence of riboflavin,xe2x80x9d Biochimica et Biophysica Acta 103:360-363; and Speck, W. T. et al. (1976), xe2x80x9cFurther Observations on the Photooxidation of DNA in the Presence of Riboflavin,xe2x80x9d Biochimica et Biophysica Acta 435:39-44. Binding of lumiflavin (7,8,10-trimethylisoalloxazine) to DNA is discussed in Kuratomi, K., et al. (1977), xe2x80x9cStudies on the Interactions between DNA and Flavins,xe2x80x9d Biochimica et Biophysica Acta 476:207-217. Hoffmann, M. E., et al. (1979), xe2x80x9cDNA Strand Breaks in Mammalian Cells Exposed to Light in the Presence of Riboflavin and Tryptophan,xe2x80x9d Photochemistry and Photobiology 29:299-303 describes the use of riboflavin and tryptophan to induce breaks in DNA of mammalian cells after exposure to visible fluorescent light or near-ultraviolet light. The article states that these effects did not occur if either riboflavin or tryptophan was omitted from the medium. DNA strand breaks upon exposure to proflavine and light are reported in Piette, J. et al. (1979), xe2x80x9cProduction of Breaks in Single- and Double-Stranded Forms of Bacteriophage "PHgr"X174 DNA by Proflavine and Light Treatment,xe2x80x9d Photochemistry and Photobiology 30:369-378, and alteration of guanine residues during proflavine-mediated photosensitization of DNA is discussed in Piette, J., et al. (1981), xe2x80x9cAlteration of Guanine Residues during Proflavine Mediated Photosensitization of DNA,xe2x80x9d Photochemistry and Photobiology 33:325-333.
J. Cadet, et al. (1983), xe2x80x9cMechanisms and Products of Photosensitized Degradation of Nucleic Acids and Related Model Compounds,xe2x80x9d Israel J. Chem. 23:420-429, discusses the mechanism of action by production of singlet oxygen of rose bengal, methylene blue, thionine and other dyes, compared with mechanisms not involving production of singlet oxygen by which nucleic acid attack by flavin or pteron derivatives proceeds. Riboflavin is exemplified in this disclosure as having the ability to degrade nucleic acids. Korycka-Dahl, M., et al. (1980), xe2x80x9cPhotodegradation of DNA with Fluorescent Light in the Presence of Riboflavin, and Photoprotection by Flavin Triplet-State Quenchers,xe2x80x9d Biochimica et Biophysica Acta 610:229-234 also discloses that active oxygen species are not directly involved in DNA scission by riboflavin. Peak, J. G., et al. (1984), xe2x80x9cDNA Breakage Caused by 334-nm Ultraviolet Light is Enhanced by Naturally Occurring Nucleic Acid Components and Nucleotide Coenzymes,xe2x80x9d Photochemistry and Photobiology 39:713-716 further explores the mechanism of action of riboflavin and other photosensitizers. However, no suggestion is made that such photosensitizers be used for decontamination of medical fluids.
Apparatuses for decontamination of blood have been described in U.S. Pat. No. 5,290,221 issued Mar. 1, 1994 to Wolfe, Jr., et al. and U.S. Pat. No. 5,536,238 issued Jul. 16, 1996 to Bischof. U.S. Pat. No. 5,290,221 discloses the irradiation of fluid in a relatively narrow, arcuate gap. U.S. Pat. No. 5,536,238 discloses devices utilizing optical fibers extending into a filtration medium. Both patents recommend as photosensitizers benzoporphryin derivatives which have an affinity for cell walls. The PCT publication WO 80/04930 which is incorporated by reference herein and which claims priority from U.S. patent application Ser. No. 09/119,666, filed Jul. 21, 1998, and U.S. patent application Ser. No. 09/357,188, filed Jul. 20, 1999, discloses the use of riboflavin as a photosensitizer.
All publications referred to herein are hereby incorporated by reference to the extent not inconsistent herewith.
The instant invention relates to the addition of a photosensitizer to treat fluid or other material to inactivate at least some of the microorganisms and white cells which may be present therein.
One mechanism by which these photosensitizers may inactivate microorganisms is by interfering with nucleic acids, so as to prevent replication of the nucleic acid.
As used herein, the term xe2x80x9cinactivation of a microorganismxe2x80x9d means totally or partially preventing the microorganism from replicating, either by killing the microorganism or otherwise interfering with its ability to reproduce.
Microorganisms include viruses (both extracellular and intracellular), bacteria, bacteriophages, fungi, blood-transmitted parasites, and protozoa. Exemplary viruses include acquired immunodeficiency (HIV) virus, hepatitis A, B and C viruses, sinbis virus, cytomegalovirus, vesicular stomatitis virus, herpes simplex viruses, e.g. types I and II, human T-lymphotropic retroviruses, HTLV-III, lymphadenopathy virus LAV/IDAV, parvovirus, transfusion-transmitted (TT) virus, Epstein-Barr virus, and others known to the art. Bacteriophages include "PHgr"X174, "PHgr"6, xcex, R17, T4, and T2. Exemplary bacteria include P. aeruginosa, S. aureus, S. epidermidis, L. monocytogenes, E. coli, K. pneumonia and S. marcescens. 
Inactivation of white blood cells may be desirable when suppression of immune or autoimmune response is desired, e.g., in processes involving transfusion of red cells, platelets or plasma when donor white blood cells may be present.
Platelet additive solutions comprising endogenous photosensitizers and endogenously-based derivative photosensitizers are provided herein. Platelet additive solutions known to the art may be used for this purpose and include those disclosed in U.S. Pat. Nos. 5,908,742; 5,482,828; 5,569,579; 5,236,716; 5,089,146; and 5,459,030. Such platelet additive solutions may contain physiological saline solution, buffer, and other components including magnesium chloride and sodium gluconate. The pH of such solutions is preferably between about 7.0 and 8.0. These solutions are useful as carriers for platelet concentrates to allow maintenance of cell quality and metabolism during storage, reduce plasma content and extend storage life. The photosensitizer may be present in such solutions at any desired concentration from about 1 xcexcM to the solubility of the photosensitizer in the solution, and preferably between about 8 xcexcM and about 50 xcexcM, more preferably about 10 xcexcM. One platelet additive solution comprises sodium acetate, sodium chloride, sodium gluconate, 1.5 mM magnesium chloride, 1 mM sodium phosphate 14 xcexcM 7,8-dimethyl-10-ribityl-isoalloxazine and preferably also 6 mM ascorbate.
In the preferred embodiment, a novel rather than a known platelet solution is used and such novel platelet additive solution has a pH between about 7.0 and 8.0 and comprises 63-95 mM of bicarbonate, 33-52 mM of glucose, 5.1-8.8 mM of citrate, and a preferred endogenous photosensitizer as defined below.
Materials which may be treated and stored using the solutions of this invention include any materials which are adequately permeable to photoradiation to provide sufficient light to achieve viral inactivation, or which can be suspended or dissolved in fluids which have such permeability to photoradiation. Examples of such materials are whole blood and aqueous compositions containing biologically active proteins derived from blood or blood constituents. Packed red cells, platelets and plasma (fresh or fresh frozen plasma) are exemplary of such blood constituents. In the preferred embodiment, platelets are treated and stored using the preferred solution of this invention. In addition, therapeutic protein compositions containing proteins derived from blood, such as fluids containing biologically active protein useful in the treatment of medical disorders, e.g. factor VIII, Von Willebrand factor, factor IX, factor X, factor XI, Hageman factor, prothrombin, anti-thrombin III, fibronectin, plasminogen, plasma protein fraction, immune serum globulin, modified immune globulin, albumin, plasma growth hormone, somatomedin, plasminogen streptokinase complex, ceruloplasmin, transferrin, haptoglobin, antitrypsin and prekallikrein may be treated by the decontamination methods of this invention. Other fluids which could benefit from the treatment of this invention are peritoneal solutions used for peritoneal dialysis which are sometimes contaminated during connection, leading to peritoneal infections.
The term xe2x80x9cbiologically activexe2x80x9d means capable of effecting a change in a living organism or component thereof. xe2x80x9cBiologically activexe2x80x9d with respect to xe2x80x9cbiologically active proteinxe2x80x9d as referred to herein does not refer to proteins which are part of the microorganisms being inactivated. Similarly, xe2x80x9cnon-toxicxe2x80x9d with respect to the photosensitizers means low or no toxicity to humans and other mammals, and does not mean non-toxic to the microorganisms being inactivated. xe2x80x9cSubstantial destructionxe2x80x9d of biological activity means at least as much destruction as is caused by porphyrin and porphyrin derivatives, metabolites and precursors which are known to have a damaging effect on biologically active proteins and cells of humans and mammals. Similarly, xe2x80x9csubstantially non-toxicxe2x80x9d means less toxic than porphyrin, porphyrin derivatives, metabolites and precursors that are known for blood sterilization.
The term xe2x80x9cblood productxe2x80x9d as used herein includes blood constituents and therapeutic protein compositions containing proteins derived from blood as defined above. Fluids containing biologically active proteins other than those derived from blood may also be treated by the methods of this invention.
The endogenous photosensitizers and endogenously-based photosensitizer derivatives used in this invention do not substantially destroy the biological activity of fluid components other than microorganisms. As much biological activity of these components as possible is retained, although in certain instances, when the methods are optimized, some loss of biological activity, e.g., denaturization of protein components, must be balanced against effective decontamination of the fluid. So long as fluid components retain sufficient biological activity to be useful for their intended or natural purposes, their biological activities are not considered to be xe2x80x9csubstantially destroyed.xe2x80x9d
The photosensitizers useful in this invention include any photosensitizers known to the art to be useful for inactivating microorganisms. A xe2x80x9cphotosensitizerxe2x80x9d is defined as any compound which absorbs radiation of one or more defined wavelengths and subsequently utilizes the absorbed energy to carry out a chemical process. Examples of such photosensitizers include porphyrins, psoralens, dyes such as neutral red, methylene blue, acridine, toluidines, flavine (acriflavine hydrochloride) and phenothiazine derivatives, coumarins, quinolones, quinones, and anthroquinones. Photosensitizers of this invention may include compounds which preferentially adsorb to nucleic acids, thus focusing their photodynamic effect upon microorganisms and viruses with little or no effect upon accompanying cells or proteins. Other photosensitizers are also useful in this invention, such as those using singlet oxygen-dependent mechanisms. Most preferred are endogenous photosensitizers. The term xe2x80x9cendogenousxe2x80x9d means naturally found in a human or mammalian body, either as a result of synthesis by the body or because of ingestion as an essential foodstuff (e.g. vitamins) or formation of metabolites and/or byproducts in vivo. Examples of such endogenous photosensitizers are alloxazines such as 7,8-dimethyl-10-ribityl isoalloxazine (riboflavin), 7,8,10-trimethylisoalloxazine (lumiflavin), 7,8-dimethylalloxazine (lumichrome), isoalloxazine-adenine dinucleotide (ravine adenine dinucleotide [FAD]), alloxazine mononucleotide (also known as flavine mononucleotide [FMN] and riboflavine-5-phosphate), vitamin Ks, vitamin L, their metabolites and precursors, and napththoquinones, naphthalenes, naphthols and their derivatives having planar molecular conformations. The term xe2x80x9calloxazinexe2x80x9d includes isoalloxazines. Endogenously-based derivative photosensitizers include synthetically derived analogs and homologs of endogenous photosensitizers which may have or lack lower (1-5) alkyl or halogen substituents of the photosensitizers from which they are derived, and which preserve the function and substantial non-toxicity thereof When endogenous photosensitizers are used, particularly when such photosensitizers are not inherently toxic or do not yield toxic photoproducts after photoradiation, no removal or purification step is required after decontamination, and treated product can be directly returned to a patient""s body or administered to a patient in need of its therapeutic effect. Preferred endogenous photosensitizers are: 
The photosensitizer of this invention is mixed with the material to be decontaminated. Mixing may be done by simply adding the photosensitizer in dry or aqueous form or the solution of this invention containing the photosensitizer to a fluid to be decontaminated. The material to be decontaminated to which photosensitizer has been added can be flowed past a photoradiation source, and the flow of the material generally provides sufficient turbulence to distribute the photosensitizer throughout the fluid to be decontaminated. Alternatively, the fluid and photosensitizer can be placed in a photopermeable container and irradiated in batch mode, preferably while agitating the container to fully distribute the photosensitizer and expose all the fluid to the radiation.
The amount of photosensitizer to be mixed with the fluid will be an amount sufficient to adequately inactivate microorganisms therein, but less than a toxic (to humans or other mammals) or insoluble amount. As taught herein, optimal concentrations for desired photosensitizers may be readily determined by those skilled in the art without undue experimentation. Preferably the photosensitizer is used in a concentration of at least about 1 xcexcM up to the solubility of the photosensitizer in the fluid, and preferably about 10 xcexcM. For 7,8 dimethyl-10-ribityl isoalloxazine a concentration range between about 1 xcexcM and about 160 xcexcM is preferred, preferably about 8 xcexcM-50 xcexcM.
The fluid containing the photosensitizer is exposed to photoradiation of the appropriate wavelength to activate the photosensitizer, using an amount of photoradiation sufficient to activate the photosensitizer as described above, but less than that which would cause non-specific damage to the biological components or substantially interfere with biological activity of other proteins present in the fluid. The wavelength used will depend on the photosensitizer selected, as is known to the art or readily determinable without undue experimentation following the teachings hereof. Preferably the light source is a fluorescent or luminescent source providing light of about 300 nm to about 700 nm, and more preferably about 340 nm to about 650 nm of radiation. Wavelengths in the ultraviolet to visible range are useful in this invention. The light source or sources may provide light in the visible range, light in the ultraviolet range, or a mixture of light in the visible and ultraviolet ranges.
The activated photosensitizer is capable of inactivating the microorganisms present, such as by interfering to prevent their replication. Specificity of action of the photosensitizer is conferred by the close proximity of the photosensitizer to the nucleic acid of the microorganism and this may result from binding of the photosensitizer to the nucleic acid. xe2x80x9cNucleic acidxe2x80x9d includes ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). Other photosensitizers may act by binding to cell membranes or by other mechanisms. The photosensitizer may also be targeted to the microorganism to be inactivated by covalently coupling to an antibody, preferably a specific monoclonal antibody to the microorganism.
The fluid containing the photosensitizer may be irradiated in a photopermeable container. The term xe2x80x9ccontainerxe2x80x9d refers to a closed or open space, which may be made of rigid or flexible material, e.g., may be a bag or box or trough. It may be closed or open at the top and may have openings at both ends, e.g., may be a tube or tubing, to allow for flow-through of fluid therein. A cuvette has been used to exemplify one embodiment of the invention involving a flow-through system. Collection bags, such as those used with the Trima(trademark) Spectra(trademark) and apheresis systems of Cobe Laboratories, Inc., and permeable bags suitable for containing fluid have been used to exemplify another embodiment involving batch-wise treatment of the fluid.
The term xe2x80x9cphotopermeablexe2x80x9d means the material of the container is adequately transparent to photoradiation of the proper wavelength for activating the photosensitizer. In the flow-through system, the container has a depth (dimension measured in the direction of the radiation from the photoradiation source) sufficient to allow photoradiation to adequately penetrate the container to contact photosensitizer molecules at all distances from the light source and ensure inactivation of microorganisms in the fluid to be decontaminated, and a length (dimension in the direction of fluid flow) sufficient to ensure a sufficient exposure time of the fluid to the photoradiation. The materials for making such containers, depths and lengths of containers may be easily determined by those skilled in the art without undue experimentation following the teachings hereof, and together with the flow rate of fluid through the container, the intensity of the photoradiation and the absorptivities of the fluid components, e.g., plasma, platelets, red blood cells, will determine the amount of time the fluid needs to be exposed to photoradiation. For 7,8-dimethyl-10-ribityl isoalloxazine, a preferred amount of radiation is between about 1 J/cm2 to 200 J/cm2.
The fluid to be treated also may be placed in a photopermeable container which is agitated and exposed to photoradiation for a time sufficient to substantially inactivate the microorganisms. The photopermeable container is preferably a blood bag made of transparent or semitransparent plastic, and the agitating means is preferably a shaker table. The photosensitizer may be added to the container in dry form as a powder, tablet, capsule or pill or in liquid form and the container agitated to mix the photosensitizer with the fluid and to adequately expose all the fluid to the photoradiation to ensure inactivation of microorganisms. In the preferred embodiment, the photosensitizer is combined with the other constituents of the additive solution and such additive solution containing photosensitizer is added to the fluid to be treated. It is also contemplated that exposure of the fluid to photoradiation can also occur without agitation of the photopermeable container or that such agitation can occur prior to exposure.
The photosensitizer may be added to the photopermeable container before sterilization of such container or after sterilization. When the preferred additive solution containing photosensitizer is used, it is preferred that the glucose and photosensitizer mixture be separated from the citrate and bicarbonate mixture during sterilization to prevent degradation of the glucose and photosensitizer. More specifically, the glucose/photosensitizer mixture should be sterilized at a lower pH than that of the citrate/bicarbonate mixture.
This invention also comprises fluids comprising biologically active protein, blood or blood constituents and also containing endogenous photosensitizer, or endogenously based derivative photosensitizer, and an additive solution. The fluid may also contain inactivated microorganisms.
Any means for adding the photosensitizer or the additive solution containing photosensitizer to the fluid to be decontaminated and for placing the fluid in the photopermeable container known to the art may be used, such means typically including flow conduits, ports, reservoirs, valves, and the like. It may be desirable that the system include means such as pumps or adjustable valves for controlling the flow of the photosensitizer into the fluid to be decontaminated so that its concentration may be controlled at effective levels as described above. The photosensitizer can be added to the fluid to be decontaminated in a pre-mixed aqueous solution, e.g., in water or storage buffer solution. Preferably the photosensitizer is added to the fluid to be decontaminated in aqueous form, but it could also be added as a dry medium in powder, pill, tablet or capsule form.
In one embodiment the fluid is placed in a photopermeable container such as a blood bag, e.g. used with the apheresis system described in U.S. Pat. No. 5,653,887, and agitated while exposing to photoradiation. Suitable bags include collection bags as described herein. Collection bags used in the Spectra(trademark) system or Trima(trademark) apheresis system of Cobe Laboratories, Inc. are especially suitable. Shaker tables are known to the art, e.g. as described in U.S. Pat. No. 4,880,788. The bag is equipped with at least one port for adding fluid thereto. In one embodiment an additive solution containing the photosensitizer, preferably 7,8-dimethyl-10 ribityl-isoalloxazine, is added to the fluid-filled bag in liquid form. The bag is then placed on a shaker table and agitated under photoradiation until substantially all the fluid has been exposed to the photoradiation. Alternatively, the bag may be prepackaged with powdered photosensitizer and/or powdered additive solution constituents contained therein. The fluid to be decontaminated may then be added through the appropriate port.
Decontamination systems as described above may be designed as stand-alone units or may be easily incorporated into existing apparatuses known to the art for separating or treating blood being withdrawn from or administered to a patient. For example, such blood-handling apparatuses include the COBE Spectra(trademark) or TRIMA(copyright) apheresis systems, available from Cobe Laboratories, Inc., Lakewood, Colo., or the apparatuses described in U.S. Pat. No. 5,653,887 and U.S. Ser. No. 08/924,519 filed Sep. 5, 1997 (PCT Publication No. WO 99/11305) of Cobe Laboratories, Inc. as well as the apheresis systems of other manufacturers. The decontamination system may be inserted just downstream of the point where blood is separated and collected just prior to insertion of blood product into a patient, or at any point after separation of blood constituents. The photosensitizer is added to blood components along with the storage or additive solution in a preferred embodiment. It is further contemplated that separate irradiation sources and cuvettes could be placed downstream from collection points for platelets, for plasma and for red blood cells. The use of three separate blood decontamination systems is preferred to placement of a single blood decontamination system upstream of the blood separation vessel of an apheresis system because the lower flow rates in the separate component lines allows greater ease of irradiation. In other embodiments, decontamination systems of this invention may be used to process previously collected and stored blood products.
The endogenous photosensitizers and endogenously-based derivative photosensitizers disclosed herein can be used in pre-existing blood component decontamination systems as well as in the decontamination system disclosed herein. For example, the endogenous photosensitizers and endogenously-based derivative photosensitizers of this invention can be used in the decontamination systems described in U.S. Pat. Nos. 5,290,221 and 5,536,238.